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How to stop Multiple Sclerosis in Mice: step 1

Administering neural progenitor cells (NPC) is one of the most promising ways to treat multiple sclerosis. Jingwu Zhang and co-workers1 now report in Cell how these cells release the cytokine leukaemia inhibitory factor (LIF) that reduces disease progression.

Multiple sclerosis is an autoimmune disease that attacks the central nervous system causing inflammation, loss of myelin sheets, and the eventual degeneration of neurons. These symptoms are linked to specialised cells of the immune system called helper T cells. A subset of helper T cells, T helper 17 (Th17), release interleukin-17 (IL-17), a key inflammatory factor in the development of multiple sclerosis.

The role of IL-17 in disease progression was cleared observed in several studies performed using mice with chemically induced multiple sclerosis (experimental autoimmune encephalomyelitis; EAE). Removal of IL-17 delayed disease onset and reduced its severity. On the other hand, the disease was worsened by the increased expression of IL-17 or a greater number of Th17 cells.

So, how do NPCs reduce multiple sclerosis? Currently, they are thought to migrate to damaged neurons and differentiate into myelin sheets that protect the neurons. However, only 5–10% of NPCs form myelin sheets. To discover any additional mechanisms, the researchers injected NPC cells into diseased mice. The cells migrated to the spleen and reduced symptoms by inhibiting Th17 cell formation, which suggested that the NPC cells must release a secreted factor. This was confirmed by treating the mice with irradiated NPC cells and an NPC cell supernatant, which also inhibited the disease.

To identify the factor responsible, the researchers tested several NPC secreted proteins on Th17 cell differentiation, identifying LIF. Recombinant LIF was then injected into diseased mice that suppressed disease progression. These mice had lower levels of Th17 cells, but normal levels of other immune cells. Conversely, inhibiting LIF with a neutralising antibody reserved this recovery.

Further studies showed that LIF works by binding to CD4+ T cells and preventing their differentiation into Th17 cells. Upon binding to the LIF receptor, LIF triggers the extracellular signal-regulated MAP kinase (ERK) signalling pathway that increases the level of suppressor of cytokine signaling 3 (SOCS3). SOCS3 prevents the phosphorylation of Janus kinase-2 (JAK-2) and signal transducer and activator of transcription 3 (STAT3) inhibiting differentiation of the Th17 cells.

Finally, the researchers tested whether LIF has the same role in humans. They first purified healthy CD4+ T cells and then added either recombinant human LIF or NPC supernatant. Similarly to the mouse, these treatments prevented Th17 cell differentiation, which was negated by adding a LIF-neutralising antibody. These results were repeated in cells from 18 subjects with multiple sclerosis, confirming their relevance to human disease.

This important work shows how LIF inhibits Th17 differentiation in both mice and human models. The advantage of LIF is its selectivity — it specifically inhibits Th17 cells and does not affect other immune cells. Other studies specify how LIF can stimulate a neural repair mechanism, which also improves neuronal survival. The researchers suggest that this dual action makes LIF a strong candidate to develop a better therapy to treat multiple sclerosis.